ToxSci Advance Access originally published online on August 4, 2005
Toxicological Sciences 2005 88(1):161-171; doi:10.1093/toxsci/kfi274
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Published by Oxford University Press 2005.
Neurochemical Effects of Chronic Dietary and Repeated High-Level Acute Exposure to Chlorpyrifos in Rats
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* Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Departments of Pharmacology, Neurology, and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Received June 23, 2005; accepted July 27, 2005
Very little is known about the effects of chronic exposure to relatively low levels of anticholinesterase insecticides or how the effects of chronic exposure compare to those of higher, intermittent exposure. To that end, adult male rats were fed an anticholinesterase insecticide, chlorpyrifos (CPF), for 1 year at three levels of dietary exposure: 0, 1, or 5 mg/kg/day (0+oil, 1+oil, and 5+oil). In addition, half of each of these groups also received a bolus dosage of CPF in corn oil ("spiked" animals; 60 mg/kg initially and 45 mg/kg thereafter) every 2 months (0+CPF, 1+CPF, 5+CPF). Animals were analyzed after 6 or 12 months of dosing, and again 3 months after cessation of dosing (i.e., "recovery" animals—six experimental groups with n = 4–6/group/time point). Cholinesterase (ChE) activity was measured in retina, whole blood, plasma, red blood cells, diaphragm, and brain [pons, striatum, and the rest of the brain (referred to simply as "brain")]. Muscarinic receptor density was assessed in retina, pons, and brain, whereas dopamine transporter density and the levels of dopamine and its metabolites were assessed in striatum. Cholinesterase activity at 6 and 12 months was not different in any of the tissues, indicating that a steady state had been reached prior to 6 months. The 1+oil group animals showed ChE inhibition only in the blood, whereas the 5+oil group exhibited 
50% ChE inhibition in all tissues tested. One day after the bolus dose, all three groups (0+CPF, 1+CPF, 5+CPF) showed 70% ChE inhibition in all tissues. Muscarinic receptor density decreased only in the brain of the 5+oil and 5+CPF groups, whereas dopamine transporter density increased only at 6 months in all three spiked groups. Striatal dopamine or dopamine metabolite levels did not change at any time. Three months after CPF dosing ended, all end points had returned to control levels. These data indicate that, although chronic feeding with or without intermittent spiked dosages with CPF produces substantial biochemical changes in a dose- and tissue-related manner, there are no persistent biochemical changes.
Key Words: chlorpyrifos; rat; chronic; cholinesterase; muscarinic; dopaminergic.
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